Although a variety of delivery systems are being developed for different routes of administration like oral, parenteral, nasal and transdermal, etc. the oral route remains attractive because this mode of administration is an easy, convenient, noninvasive and familiar method of drug delivery. The majority of prescribed drugs are designed for oral application since they can be self-administered by the patient without hospitalization. Oral dosage forms are designed according to the nature of the drug, the nature of application and the need for any special effects as desired in the delivery system. The common oral dosage forms include: liquid mixtures like solutions, suspensions, solid dosage forms like tablets and capsules and liquid filled capsules etc. The solid dosage forms are further modified depending on the therapeutic action desired like controlled, extended or delayed release. However, patients at the extremes of age, such as children and the elderly, often experience difficulty in swallowing solid oral dosages forms. For these patients the drugs are mostly provided in liquid dosage forms such as solutions, emulsions and suspensions. These dosage forms usually lead to perceptible exposure of the active drug ingredient to the taste buds, which is a very serious problem when the drug has an extremely unpleasant or bitter taste.
The bitter taste of the drugs, which are orally administered, is disadvantageous in several aspects. Taste is an important parameter governing the compliance. The disagreeable taste of drugs causes difficulties in swallowing or causes patients to avoid their medication, thereby resulting in low patient compliance. Conventional taste masking techniques such as use of sweeteners, amino acids, flavoring agents are often unsuccessful in masking the taste of the highly bitter drugs like quinine, barberin, etoricoxib, antibiotics like levofloxacin, ofloxacin, sparfloxacin, gatifloxacin, ciprofloxacin, cefuroxime axetil, erythromycin and clarithromycin. Thus taste-masking technologies are considered important and are developed by many researchers.
Taste masking is a major problem when the drugs are extremely unpleasant and bitter. Further, this problem is not only restricted to the liquid oral compositions like solutions, dry syrups and suspensions but may also be encountered during the formulation of chewable tablets or dispersible tablets wherein these dosage forms usually lead to perceptible exposure of active ingredient to taste buds.
The main scientific difficulties associated with oral drug delivery apart from taste masking, relate to a variety of changes the active ingredient undergoes during formulation process and also due to the physicochemical environment that these active ingredients encounter when ingested e.g. the low pH of stomach ranging to the high pH of the small intestine, and the effect of these media on the stability, dissolution and bioavailability of the active ingredient. For many drugs the region of the gastrointestinal tract, which provides an effective absorption window, is quite limited. For example, the uptake may be limited to a particular region of the small intestine or limited only to the upper gastric cavity. Some drugs have a tendency to change their polymorphic forms during formulation or in contact of the gastric fluid thereby affecting their bioavailability. The physiochemical properties of the drug affecting the performance of the delivery system are drug solubility, dissolution rate, particle size, lipophilicity, stability and polymorphism and amorphism.
Certain drugs pose challenges during formulation due to their physicochemical characteristics. Cefuroxime axetil exhibits the tendency to gel in contact with the aqueous media necessitating that the dosage form disintegrates into particles rapidly and releases the drug at a faster rate before the gelling occurs in vivo. The amorphous form of cefuroxime axetil exhibits greater bioavailability than the crystalline form. Also the drug shows a tendency to crystallize when in contact with the solvent for long time again making it necessary to dissolve rapidly from the composition. Another problem associated with cefuroxime axetil relates to extremely bitter taste of the drug making it necessary to formulate cefuroxime axetil in a coated delivery system to make it palatable. Celecoxib has an extremely low aqueous solubility and is not readily dissolved and dispersed for rapid absorption in the gastrointestinal tract. Further celecoxib crystals present problems like low bulk density, poor flow characteristics, electrostatic and cohesive properties making it difficult to formulate. The amorphous form of celecoxib exhibits rapid dissolution and also higher bioavailability but it tends to crystallize in contact with the aqueous media. Etoricoxib, another molecule from the COX 2 inhibitor family is also associated with extremely bitter taste. Cefuroxime axetil, a second generation cephalosporin antibiotic and celecoxib, from the class of COX 2 inhibitors both have relatively high dose requirement further increasing difficulty in administering the therapeutically effective dose. Such active molecules which pose formulation problems and are required to be administered as rapid release formulations to overcome the low bioavailability, need a protective polymer coating which releases the active ingredient at a rapid rate without compromising the bioavailability, inhibits the crystallization and also masks the bitter taste of the active ingredient.
Various methods for taste masking have been tried earlier, which include use of ion exchange resins, complexation with pharmaceutically acceptable excipients and coating of drugs by lipids and various polymeric materials. Of these, coating is the most widely used technique for taste masking. Coating of active ingredient can be done by any technique known in the art like microencapsulation, hot melt granulation, wurster coating, spray drying.
One of the approaches for taste masking is the use of ion exchange resins. Various anionic resins like Duolite AP143/1083™ (cholestyramine resin USP), Cationic resin like Amberlite IRP 64™ (copolymer of methacrylic acid crosslinked with divinyl benzene) and Dowex (based on polystyrenesulfonic acid cross linked with divinylbenzene) are used. U.S. Pat. No. 6,514,492, assigned to Schering Plough discloses the use of ion exchange resin AMBERLITE.RTM. IRP 69™ for taste masking of quinolone derivatives thereby eliminating the extreme bitterness of the quinolones in oral liquid formulation.
Patent application WO 01/70194 discloses a fast dissolving orally consumable film adapted to adhere to and dissolve in mouth of the consumer. The film is composed of an ion exchange resin, amberlite and a water soluble polymer pullulan as taste masking agent for the bitter drug, dextromethorphan. The film adheres to the oral cavity and dissolves to deliver the active ingredient. The use of the water soluble polymer in the formulation would restrict the use of such delivery system if the taste masking was desired for liquid oral preparation. Further such delivery systems may not be well accepted in case of pediatric and geriatric preparations where patient compliance is very important.
U.S. Pat. No. 6,001,392 discloses a controlled release syrup suspension for the oral administration containing dextromethorphan, adsorbed on to a polystyrene sulfonate ion exchange resin. The drug polymer complex is coated by a mixture of ethyl cellulose or ethyl cellulose latexes with plasticizers and water dispersible polymers such as SURELEASE™. For the drugs where immediate release is required for rapid action, the controlled release of the active ingredient may not be favored and a delay in release may also be of concern for drugs having a limited absorption window.
The use of ion exchange resin to adsorb drugs containing amino groups for taste masking has found limited applicability in masking the taste of highly bitter drugs and also where the drug is to be dispersed in a liquid oral composition for long duration of time.
Complexation is yet another method for taste masking of bitter drugs. U.S. Pat. No. 4,808,411 discloses a taste masked composition comprising 25 to 95% of erythromycin and about 75 to 5% of carbomer where the drug and carbomer are held together by ionic interactions between erythromycin and carbomer. The complex is further coated with a functional polymer, hydroxy propyl methylcellulose phthalate to make preparation palatable. Erythromycin is released slowly from the complex to avoid a significant perception of bitterness in the mouth. It is clear that slow release, not fast release of bitter medicament is achieved as disclosed in the patent. But complexing alone is not sufficient enough to taste mask and coating with functional polymers is required to attain desired palatability and proper selection of complexing agent is vital since drug release should not be compromised.
Coating of drugs is another method but this alone may prove effective only for moderately bitter drugs or in products where coated particles are formulated as aqueous preparations before administration or are formulated in nonaqueous medium.
Patent Application WO 02/092106 discloses a taste-masked composition comprising polycarbophil and a macrolide antibiotic, clarithromycin. The complex is further coated with an acid resistant polymer Eudragit L100 55™, releasing the drug in the intestine. For certain drugs the bioavailability may not be altered by the use of enteric coating where the drug is released in the small intestine, but the drugs with a narrow absorption window restricted to the upper gastric region, the use of enteric coating may alter the bioavailability. European Patent application EP 0409254 discloses an oral particulate preparation with unpleasant taste being masked using ethyl cellulose and a water swelling agent where the active is released rapidly from the said formulation.
U.S. Pat. No. 5,635,200 discloses a taste-masked preparation of bitter drug ranitidine by a lipid coating and dispersion of these coated particles in the nonaqueous media. U.S. Pat. No. 4,865,851 discloses another method for taste masking highly bitter 1 acetoxy ethyl ester of cefuroxime in particulate form being coated with an integral coating of lipid or a mixture of lipids which serves to mask the taste. The taste masking coating using lipids requires that the melting point of the lipid should be sufficiently high to prevent melting in the mouth and should not be so high that active ingredient itself melts or is chemically degraded. Cefuroxime axetil in a substantially amorphous form with maximum bioavailability has a low melting point of about 70° C. and the difference in the melting of the lipid and drug is very marginal. Also the temperature at which the mixture is atomized is higher than the melting of the lipid. Lipid-based microencapsulation requires a highly sophisticated hot melt granulation process for producing fine particles without adversely affecting the drug molecule.
British Patent 2081092 also discloses a lipid coating for the purpose of taste masking. It was however found that wax coating resulted in poor dissolution of the active ingredients in the alimentary tract. Further the patent discloses a technique to overcome this problem by mixing the waxes with a water swellable polymer. Again the use of the water swellable polymer referred to in the patent makes it less appropriate for the liquid orals like suspensions and dry syrup.
U.S. Pat. No. 5,286,489 describes a porous drug polymer matrix formed by admixing a bitter tasting active ingredient and a methyl methacrylate ester copolymer in at least a 1:1 weight ratio of active ingredient to copolymer, effective to mask the taste of the drug. None of the examples described in the patent disclose the effect of these polymers on the release of the drug from the matrix. Yet from the teaching in the art it is anticipated that the drug release is retarded from the matrix described herein.
Patent Application WO 00/56266 discloses the use of a high viscosity swellable polymer carbomer, in combination with film forming polymethacrylates and channelising agents for taste masking of bitter drugs. The addition of the water swellable polymer aids in the fast release of the active ingredient in the gastric media.
In yet another Patent Application WO 00/76479 a taste masking composition, using a combination of two enteric polymers comprising methacrylic acid copolymer and a phthalate polymer is disclosed. The patent discloses the use of the channelising agents, which comprise the water soluble or water swellable materials to aid the release of the active ingredient. The enteric polymers as disclosed in the patent are known to release the active ingredient in the alkaline pH where the polymers are soluble. The release of the active ingredient will be delayed due to the use of the enteric polymers and in case of the medicaments having a narrow absorption window limited to upper gastrointestinal tract. Such system would therefore be of limited use.
Microencapsulation of highly bitter drug cefuroxime axetil for taste masking is disclosed by M. Cuna et. al (M. Cuna, M. L. Lorenzo, J. L. Vila-Jato, D. Torres, M. J. Alonso, Acta Technologiae et Legis Medicamenti. volume VII, N.3, 1996) using different polymeric materials like cellulose acetate trimellitate, HPMCP-50, HPMCP-55 with the final aim to mask the taste and assuring its release in the intestinal cavity. Alonso et al (M. J. Alonso, M. L Lorenzo-Lamosa, M. Cuna, J. L. Vila-Jato and D. Torres, Journal Microencapsulation, 1997, Volume 14, No. 5, 607-616) describe the encapsulation of cefuroxime axetil, a highly bitter drug, in pH sensitive acrylic microspheres in order to formulate a suspension dosage form. The acrylic polymers used were Eudragit E™, Eudragit RL 100™, Eudragit L100-55™. The cationic Polymer Eudragit E™ showed a negative interaction with cefuroxime axetil. The enteric polymer Eudragit L100-55™ showed a favorable release in alkaline pH.
In the above disclosures the release of cefuroxime axetil was studied in the alkaline media. On the contrary Dantzig et al (Anne H. Dantzig, Dale C. Duckworth, Linda B. Tabas, Biochimica et Biophysica Acta 1191,1994,7-13) showed that cefuroxime axetil is hydrolyzed to cefuroxime in the intestinal lumen by the esterases reducing the cefuroxime axetil concentration in the lumen and resulting in reduced absorption, and low bioavailability of Cefuroxime axetil in humans. Cefuroxime axetil already has a low bioavailability of 32-50% and any further reduction in bioavailability due to formulation aspects should be minimized.
The taste masking formulations should be so designed that the bioavailability of the drugs is not compromised and the use of certain polymers like the enteric coatings should not affect the time to peak. Further the drug should be sufficiently absorbed to ensure effective therapeutic concentration in the plasma. Vogelman et al (B. Vogelman, William A. Craig 108 (5,pt2) 835-40, Journal Pediatric 1986 & B. Vogelman, William A. Craig, S. Ebert, S. Gudmundsson, J. Leggett, J. Infect. Diseases 1988,158(4), 831-47) have established that bactericidal killing is rapid, intensive and increases proportionately to the concentration. In the presence of high concentration of the drug, the killing is complete and almost instantaneous. In some drugs rapid and complete absorption and high systemic concentration are important to elicit the desired therapeutic effect.
Extremely unpleasant tasting active ingredients may require a higher concentration of polymer to obtain the desirable level of taste masking. However this may delay the release of the active ingredient from the formulation. For certain polymers like polymethacrylates the recommended safe daily dose is 2 mg/kg of body weight (Rohm Pharma GmbH. Technical Literature, Eudragit 1990 and Hand book of Pharmaceutical Excipients published by American Pharmaceutical Association & The Pharmaceutical Society of Great Britain) there by restricting the use of higher quantities of the polymer in real life formulation to be administered to humans.
U.S. Pat. No. 5,599,556 disclose liquid formulations where the active ingredient is coated with single outer polymeric coating derived from prolamine cereal grain proteins and plasticizing agent. The bitter drug clarithromycin comixed with polyvinyl pyrrolidone is coated by prolamine to achieve taste masking and the coated particulate matter is dispersed in a suspending medium of pH greater than 6. The coatings are designed to rapidly degrade once the composition leaves mouth and reaches the stomach. Most of the pharmaceutical liquid oral compositions are formulated at a pH of 3.5-5.5 (US Pharmacopoeia/National Formulary 23/NF 18,1995). Some drugs may not be stable at the higher pH and some drugs may not be stable in extreme acidic pH and would tend to degrade over prolonged exposure.
U.S. Pat. No. 5,489,436 discloses chewable tablets made from a coated medicament where the coating is designed to be soluble at the lower pH of the stomach but relatively water insoluble at the higher pH of the mouth. The coatings comprise a polymer blend of dimethylaminoethyl methacrylate and neutral methacrylic acid ester and a cellulose ester. The above mentioned “reverse enteric” coating method of taste masking oral formulation is disclosed in connection with chewable tablets.
Patent Application WO 02/096392 discloses taste masking of highly water soluble drug cetrizine hydrochloride. The polymers like hydroxy propyl methyl cellulose, polyvinyl pyrrolidone, ethyl cellulose are used which effectively mask the taste of cetrizine in tablet form and release the drug immediately under the acidic conditions prevalent in stomach.
It is evident from the above disclosures, that taste masking can be achieved by various methods. The enteric polymers like eudragit L are used for taste masking but the pH of saliva is near 5.8 and these polymers solubilize at pH beyond 5.5. Thus there is a possibility of drug being partially leached. Therefore there is a need for the development of a taste masking polymer such that the bitter taste is completely masked by the polymer at the pH of saliva in mouth and in the reconstitution medium as in case of the liquid orals and further is able to protect the drug in a biologically active form, and also from the moisture in the dosage form preventing it from converting to a solvated or other polymorphic form.
The therapeutic effectiveness of a drug depends upon the ability of the dosage form to deliver the medicament to its site of action at a rate and amount sufficient to elicit the desired pharmacological response. This attribute is referred to as bioavailability. The physicochemical properties of most drugs have greatest influence on the absorption characteristics from the gastrointestinal tract. An important prerequisite for the absorption of a drug by any mechanism is that it must be present in aqueous solution. The poor bioavailability of a drug is a result of its poor aqueous solubility and slow dissolution rate in the biological fluids and poor stability of dissolved drug in the physiological fluids.
Often a chemical substance exists in different ordered states. This is referred to as polymorphism. The polymorphic form, in which the drug is present, can likewise be influenced by the processing techniques. The various crystallographic forms also include pseudo polymorphic forms. It is well known that differences due to polymorphism and pseudo polymorphism observed in certain pharmaceuticals are critical because physical and chemical properties of different crystalline forms of these pharmaceuticals vary. Pharmaceutical drugs and excipients can crystallize in more than one crystallographic form (polymorph, crystalline modifications). Although polymorphs of a substance share the same chemical formula, difference in crystalline structure can affect the physiochemical parameters of the substance such as, solubility, dissolution rate, density (Haleblain, J. K. and Mc Crone, W, Journal of Pharmaceutical Sciences, 58, (8) August, 911-929, (1969) which in turn can affect their important pharmaceutical properties such as bioavailability, stability of drug as well as formulation technology of dosage form. (Byrn, S., Pfeiffer, R., Ganey, M., Hoiberg, C., Poochikian, G., Pharmaceutical Research, 12 (7),945-954, (1995) The physically more stable polymorphic form has lowest energy state, highest melting point and least aqueous solubility. The other forms are the metastable forms, which have higher energy, low melting point and greater solubility. Since the metastable forms have greater solubility and hence greater bioavailability, they are preferred in the formulation. Drugs present in the amorphous forms have higher energy and greater aqueous solubility. The amorphous form of novobiocin has 10 times greater solubility than the crystalline form. Thus the order of dissolution of the different forms of the solid forms of drug is amorphous>metastable>crystalline.
In general, drugs, which are slightly soluble in water and have high crystallinity, have low bioavailability since they have low solubility and low dissolution rate in the gastrointestinal tract. It is well known that converting a crystalline compound into its amorphous state will substantially increase the aqueous solubility of the compound, thereby increasing its bioavailability.
When the process of in vivo drug release is slower than the process of absorption, absorption is said to be dissolution rate-limited. Since dissolution precedes absorption in the overall process, any change in the drug release or dissolution process will subsequently influence drug absorption. See for example Lieberman et al. (1989), Pharmaceutical Dosage Forms: Tablets, Vol. 1, p 34-36 Marcel Dekker, New York. It is clear, therefore, that dissolution time of a composition is one of the important fundamental characteristics for consideration when evaluating compositions intended for fast-onset delivery, particularly where drug absorption is dissolution rate-limited.
Crystalline solids, due to their highly organized, lattice-like structures typically require a significant amount of energy for dissolution. The energy required for a drug molecule to escape from a crystal, for example, is greater than is required for the same drug molecule to escape from a non-crystalline, amorphous form. As a method for obtaining amorphous substances, grinding or forming a solid dispersion is considered. In order to improve their absorbability, several methods for finely grinding drug crystals or for transforming them into amorphous substances have been examined.
Technologies have been developed to overcome the crystallization of the amorphous drugs. Simple strategies for the improvement of drug formulation like increasing the solubility of drugs and thus increasing the fraction of the dose absorbed. The techniques utilized commonly are simple barrier methods including coating and encapsulation some of them include use of the chemical carriers to increase gastrointestinal absorption for the oral delivery of such difficult to formulate molecules.
U.S. Pat. No. 4,673,564 discloses the method for the preparation of sustained release pharmaceutical composition of amorphous nicardipine obtained by friction-pulverizing crystalline nicardipine or its salt in presence of the polymer, hydroxypropylmethyl cellulose. The pulverization of crystalline nicardipine to a fine powder carried out in a ball mill or a vibrating ball mill for a period of at least 10 to 16 hours. However, the method of forming the dispersion is by, extensive and time-consuming ball-milling, and application of such methods for certain sensitive active ingredients would be limited. Patent Application WO 02/087588 discloses a composition of an amorphous cefditoren pivoxil with excellent stability and release. Amorphous cefditoren pivoxil composition is obtained by pulverizing crystalline cefditoren pivoxil in presence of a pharmaceutically acceptable organic polymer.
By fine-grinding, however, particle diameters become irregular between lots, or inter-particle force is enhanced to cause agglomeration. Drug crystals, which can become amorphous by grinding, are limited.
Other methods reported for the preparation of amorphous drug composition of a pharmaceutically active agent which is normally crystalline and sparingly water-soluble at ambient temperature and pressure, involves the dissolution or dispersion of the drug in the molten solution of a pharmaceutically acceptable vehicle and addition of a stabilization agent to retain the active ingredient in the substantially amorphous form.
In some cases it is possible to melt the crystalline active agent, holding it in the molten state for a finite time and then allow it to cool to an amorphous solid.
U.S. Pat. No. 6,171,599 discloses a method of preparation of amorphous efonidipine composition by treating efonidipine hydrochloride, hydroxy propyl methyl cellulose acetate succinate, to a cycle of heating from 85 to 160° C. followed by dipping treatment into a water-containing solution. U.S. Patent Application 20020127 relates to methods and formulations for improving the aqueous solubility of crystalline pharmaceutical compounds having low water solubility by converting them to an amorphous state that is stabilized in a granular pharmaceutical formulation. It discloses a method of improving the aqueous solubility and bioavailability of itraconazole by converting it to the amorphous state, stabilizing this state, and granulating it to form a stabilized granule. The process involves dissolving the active ingredient in the molten solution of hydrophobic vehicle.
In yet another composition of the antifungal drug intraconazole, as disclosed in U.S. Pat. No. 6,497,905, crystalline intraconazole is converted in to amorphous form by dissolving it in molten solution of glyceryl monostearate followed by addition of hydroxy propyl methyl cellulose as stabilizer and further the addition of a disintegrant and formation of the granules with gradual cooling below 5° C. or rapidly cooling the granules to the said temperature.
European Patent Application EP 0852140 discloses a method for converting a sparingly water-soluble medical substance to amorphous state which comprises mixing these components of a sparingly water-soluble medical substance, an amorphous state-inducing agent and an amorphous state-stabilizing agent, and subjecting resulting mixture to heat treatment or mechano-chemical treatment. European Patent Application EP 0462066 relates to a new physical form of gemfibrozil in solid dispersion made of polyvinyl pyrrolidone by melting gemfibrozil and then mixing with the polymer or by solvent evaporation.
All the methods disclosed above are limited to particular active ingredients, which can produce stable amorphous solids and are not degraded by the heating step. There can be some instances where not only the active agent is decomposed and the carrier is deteriorated but also active ingredient is not converted to the amorphous state sufficiently. Further, it has been known that solubility and absorbability of a slightly water-soluble compound are improved by dispersing it in a polymer to form a solid dispersion.
U.S. Pat. No. 5,445,830 discloses a highly absorbable pharmaceutical composition containing methyl 3-phenyl-2 (E)-propenyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl) pyridine-3,5-dicarboxylate in an amorphous state and a pH-sensitive copolymer of methacrylic acid or its derivatives. The inventors have disclosed that the improved solubility was achieved only if, the compound was maintained in the amorphous state, using pH-sensitive copolymers of methacrylic acid and its derivatives. Further the inventors have disclosed that using polymers such as a cellulose-type high molecular compound or polyvinylpyrrolidone or the like, the solubility of the compound was not improved. The patent discloses the blend of hydrophilic and eudragit polymers in high amount to overcome the said problem. But use of hydrophilic polymers along with the pH sensitive polymer, make such delivery system of little use in application where taste masking of an active in its amorphous form is desired where the drug particles are suspended in aqueous vehicle.
U.S. Patent Application 2002040051, discloses a solid dispersion of ipriflavone in a highly water soluble polymer. The crystalline ipriflavone is converted to an amorphous form during spray drying and the bioavailability is increased. European Patent Application EP 0838218 discloses the controlled release pharmaceutical composition containing a co precipitate of polyvinyl pyrrolidone (PVP) and nifedipine in amorphous form obtained by spray drying the solution comprising of nifedipine and PVP and releasing the drug from the co precipitate over a period of 8-24 hrs. These compositions are better suited for the sustained release system. Besides the influence of molecular weight on the transformation of the crystalline form as well as bioavailability has not been discussed.
U.S. Pat. No. 6,503,927, discloses a stable amorphous paroxetine hydrochloride composition prepared by employing an aqueous solvent medium containing an acidulant and poly vinyl pyrrolidone and drying the resulting solid dispersion. Yet another U.S. Pat. No. 6,168,805 discloses a process for preparing solid, amorphous composition comprising polyvinyl pyrrolidone. A method for obtaining amorphous paroxetine mixing paroxetine free base with water and polyvinylpyrrolidone having an average molecular weight of from about 10,000 to about 450,000; and drying to form a composition comprising amorphous paroxetine and polymer is disclosed. Poly vinyl pyrrolidone is preferred as the polymer since it does not control or delay the release of said paroxetine from a solid tablet formulation.
The compositions disclosed above making use of poly vinyl pyrrolidone are useful in delivering the active ingredients when in contact with the aqueous media but such systems cannot be formulated in the liquid dosage forms since there is a possibility of release of the active in the reconstitution media and also the recrystallization of the active ingredient in contact with the aqueous media.
Patent Application WO 00/71098 discloses the method of preparing a pharmaceutical composition comprising of amorphous paroxetine and maintain it in the amorphous form by the use of a cosolvent polyethylene glycol and a complexing agent crosspovidone. In the above invention use of the cosolvent is essential to maintain the amorphous form of paroxetine and its absence causes the recrystallization of the active ingredient even in the presence of complexing agent. Additives like polyethylene glycol, as a cosolvent will not be useful in pharmaceutical preparation where leaching of drug in aqueous media is not desired.
U.S. Pat. No. 4,857,336 discloses an osmotic delivery system for carbamazepine where the outer wall made of cellulose acetate is permeable to water but impermeable to the components of the core made up of hydroxy propyl methyl cellulose as protective colloid which inhibits the crystal growth of carbamazepine hydrate and a copolymer of vinyl pyrrolidone and vinyl acetate having a molecular weight of 60,000-15,000 as swellable hydrophilic polymer.
U.S. Pat. No. 5,980,942 discloses the drug delivery system comprising a polymer matrix made of a hydrophilic polymer Hydroxy propyl methyl cellulose, hydrophobic polymer ethyl cellulose and crystalline carbamazepine, incorporated into the polymer matrix wherein the polymer converts the carbamazepine into an amorphous anhydrous form. Further the polymer matrix inhibits the transformation of anhydrous carbamazepine into crystallized dihydrate form releasing the amorphous carbamazepine more readily at steady zero-order rate. Such polymeric matrices as mentioned in the patent are more suitable for the modified delivery. Besides these polymers do not exhibit pH dependant solubility characteristic and hence are not suitable for immediate release.
Patent Application WO 03/024426 reveals a controlled release composition comprising carvedilol where carvedilol is converted from crystalline to amorphous form during formulation of solid dispersion and also stabilized. The polymer polyethylene glycol or polyethylene oxide having a molecular weight of about 20,000 are employed in the formulation for this purpose and release drug in a controlled manner from formulation. The stabilizing agent prevents the re crystallization in the composition and increases the shelf life.
U.S. Patent Application 2002006951 discloses an orally deliverable pharmaceutical composition comprising a poorly soluble drug, celecoxib and its composite with the polymer, which has a turbidity-decreasing characteristic, poly vinyl pyrrolidone and cellulosic polymer, hydroxy propyl methylcellulose. According to the disclosure of the patent, the polymers inhibit crystallization and/or precipitation of the drug in simulated gastric fluid and on ingestion. Polymers used in this disclosure comprise HPMC having molecular weight of 150,000 and povidones having a molecular weight of 50,000. This patent discloses inhibition of recrystallization of the drug on exposure to the aqueous media in gastric tract where the drug is exposed to aqueous media for limited period of time. Also in the liquid oral preparations the aqueous medium surrounds the drug during prolonged reconstitution period.
European Patent Application 1027886 discloses a composition comprising a solid dispersion of a poorly soluble drug and stabilizing polymer. The patent discloses that the polymer having glass transition temperature of at least 100° C. measured at 50% relative humidity contributes to retain major portion of the drug in amorphous form. The term “a major portion” of the drug as disclosed herein means that at least 60% of the drug once dispersed in the dispersion is in the amorphous form, rather than the crystalline form. Amorphous drugs present in the dispersion have a tendency to recrystallize over time, and for drugs whose bioavailability is adversely affected if in crystalline form, even 20-30% drug in crystalline form would not be desired.
Cefuroxime axetil is a cephalosporin antibiotic having a high activity against a wide spectrum of Gram-positive and Gram-negative microorganisms. Antibiotics for oral administration should be in a form, which provides high bioavailability, whereby absorption into the bloodstream from the gastro-intestinal tract is maximized. For cefuroxime axetil, the prior art discloses a number of difficulties in making compositions for oral administration providing high bioavailability. Pure cefuroxime axetil can be produced in crystalline form or amorphous form. It can exist in three polymorphic forms: a crystalline form having a high melting point of about 180° C., a substantially amorphous form having a high melting point of about 135° C. and a substantially amorphous form having a low melting point of about 70° C. The crystalline form of cefuroxime axetil, which is slightly soluble in water and forms a gel upon contact with an aqueous medium, is not readily absorbable in the gastro-intestinal tract, rendering its bioavailability on oral administration very low.
Patent Application WO 99/08683 discloses a method for preparing a co precipitate of cefuroxime axetil and a water-soluble excipient like povidone. Cefuroxime axetil used in the formulation is in pure amorphous form. U.S. Pat. No. 6,107,290 discloses the thermal analysis conducted on co-precipitate. PCT application WO 99/08683 shows that a shift in the absorption peak temperature under moist condition reverts to the original position under a dry condition and the water adsorbed on the co-precipitate is judged to be bound water, which causes a physicochemical change in properties of the drug. Further, despite the use of a water-soluble excipient, the dissolution of cefuroxime axetil from the co-precipitate is not facilitated significantly and accordingly, the bioavailability of cefuroxime axetil contained in the co-precipitate is relatively low.
U.S. Pat. No. 6,107,290 discloses a non-crystalline cefuroxime axetil solid dispersant comprising silicon dioxide, water-insoluble additive like microcrystalline cellulose, cross-linked povidone, cross-linked sodium carboxymethylcellulose or a mixture thereof obtained by spray drying. Methods disclosed in this patent may be useful for solid oral dosage forms but may not be applicable for liquid oral preparation where the bitter taste may not be masked.
European Patent Application EP 1077067 discloses a solid composition of cefuroxime axetil being stabilized by zinc salt and cefuroxime axetil obtained in the pure amorphous form by spray drying. Such formulation is best suited for the solid oral dosage form.
U.S. Pat. No. 4,820,833 discloses a method of producing a substantially amorphous form of cefuroxime axetil, which is stable and provides a high level of bioavailability. The patent does not disclose methods to overcome bitter taste of the drug. U.S. Pat. No. 5,847,118 discloses a method for producing amorphous cefuroxime axetil by dissolving crystalline cefuroxime axetil in a highly polar solvent and then adding this to large quantities of water. The patent does not disclose the formulation and stability of the amorphous cefuroxime axetil therein.
U.S. Pat. No. 6,060,599 discloses a method of preparing an amorphous form of cefuroxime axetil by milling it in the presence of the pharmaceutical excipients like sodium lauryl sulfate, colloidal silicon dioxide and starch. In yet another U.S. Pat. No. 6,346,530, a method of preparing a bioavailable composition of cefuroxime axetil is disclosed which contains about 7-25% of crystalline cefuroxime axetil along with the amorphous form with the tablet exhibiting same bioavailability as the pure amorphous form.
Patent application WO 98/43980 discloses the preparation of amorphous cefuroxime axetil by dissolving crystalline cefuroxime axetil in dimethyl sulfoxide and freezing the mixture and later adding water at 5° C. The precipitate obtained is dried in vacuum. Patent Application WO 99/32124 discloses a pharmaceutical composition comprising amorphous ‘S’ cefuroxime axetil free from the ‘R’ form. Such compositions as disclosed in the patent application are claimed to be more palatable than the 1:1 racemic mixture.
Patent Application WO 99/44614 discloses a pharmaceutical composition of cefuroxime axetil and silicon dioxide or its hydrate as a micro environmental pH adjuster and as an anti gelling agent for cefuroxime axetil. Silicon dioxide acts as microenvironment pH adjuster avoiding gelling of cefuroxime axetil in the tablet core due to absorption of moisture from air and also due to the penetration of gastric fluid thereby improving the bioavailability.
Patent application WO 02/43707 discloses a taste masking tablet composition of cefuroxime axetil with a double layer film coat where the first coat serves to mask the bitter taste and the second coat delays the rupture time of the tablet beyond 40 seconds.
All the above disclosures have demonstrated the methods of obtaining an amorphous form of drugs such as cefuroxime axetil or methods to improve its bioavailability and taste masking for solid dosage forms. None of the disclosures reveal taste masking of cefuroxime axetil in a liquid oral preparation and polymers for retaining it in the amorphous form and releasing the same immediately in the stomach without compromising the bioavailability.
Our co-pending patent application No NF 403/2003 discloses and claims taste masked compositions of bitter drugs using a new polymer described and claimed in our another co-pending application No. NF 402/2003.
From the prior art it is well understood that the use of polymers along with the crystalline form of drug can convert the same drug into the amorphous form and can also be stabilized by use of polymers or co-solvent for the prevention of re-crystallization. Many of the known water soluble and swellable polymers were employed earlier for the crystallization inhibition and to improve the solubility and dissolution of poorly soluble drugs from the pharmaceutical compositions. Such polymeric systems would be of little application in taste masking of the drug in solid as well as liquid compositions.
Therefore there remains a need in the art for a means to inhibit crystallization of a drug existing in polymorphic form, in reconstitution media for liquid orals comprising of a poorly water-soluble drug, and in particular for such drugs which have a tendency to undergo polymorphic transformation in presence of the solvents.